Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10
Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10
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DOI：
10.1016/j.bbi.2014.10.015
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发表时间：
2015-03-01
影响因子：
15.1
通讯作者：
Castellano, Bernardo
中科院分区：
文献类型：
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作者：
Almolda, Beatriz;de Labra, Carmen;Castellano, Bernardo
白细胞介素-10 (IL-10) 是一种细胞因子，在不同的神经退行性和神经炎症性疾病中与中枢神经系统 (CNS) 的抗炎和保护功能密切相关。为了研究中枢神经系统局部产生IL-10的具体作用，我们创建了一种新的星形胶质细胞靶向产生IL-10的转基因小鼠品系（GFAP-IL10Tg）。在本研究中，利用免疫组织化学、分子生物学技术、电生理学和行为研究研究了基础条件下局部 CNS IL-10 产生对小胶质细胞、星形胶质细胞和神经元连接的影响。我们的结果表明，在 GFAP-IL10Tg 动物中，小胶质细胞表现出密度增加和特定的激活表型，其特征是大脑特定区域（包括海马体、皮质和小脑）的形态变化，与转基因表达的 IL-10 mRNA 水平相关。不同的是，在海马体中，小胶质细胞采用了细长的形态，其方向与锥体神经元的树突相同。此外，这种IL-10诱导的小胶质细胞表型显示某些分子的表达增加，包括Iba1、CD11b、CD16/32和F4/80标记物，CD150的“从头”表达，并且没有可检测到的CD206或MHCII水平。为了评估这种特定的激活的小胶质细胞表型是否与神经元活动的变化相关，我们对海马锥体神经元（CA3-CA1）的电生理特性进行了体内分析。我们发现 GFAP-IL10Tg 小鼠的 CA3-CA1 突触兴奋性较低且缺乏长时程增强 (LTP)。这项研究首次描述了星形胶质细胞靶向产生细胞因子 IL-10 的转基因小鼠。研究结果表明，IL-10 会诱导特定的活化小胶质细胞表型，并伴随海马 LTP 反应的变化。这种转基因动物将成为研究中枢神经系统中IL-10功能的非常有用的工具，不仅在基础条件下，而且在不同的实验损伤或诱发疾病后也是如此。 (C) 2014 Elsevier Inc. 保留所有权利。
Interleukin-10 (IL-10) is a cytokine classically linked with anti-inflammatory and protective functions in the central nervous system (CNS) in different neurodegenerative and neuroinflammatory conditions. In order to study the specific role of local CNS produced IL-10, we have created a new transgenic mouse line with astrocyte-targeted production of IL-10 (GFAP-IL10Tg). In the present study, the effects of local CNS IL-10 production on microglia, astrocytes and neuronal connectivity under basal conditions were investigated using immunohistochemistry, molecular biology techniques, electrophysiology and behavioural studies. Our results showed that, in GFAP-IL10Tg animals, microglia displayed an increase in density and a specific activated phenotype characterised by morphological changes in specific areas of the brain including the hippocampus, cortex and cerebellum that correlated with the level of transgene expressed IL-10 mRNA. Distinctively, in the hippocampus, microglial cells adopted an elongated morphology following the same direction as the dendrites of pyramidal neurons. Moreover, this IL-10-induced microglial phenotype showed increased expression of certain molecules including Iba1, CD11b, CD16/32 and F4/80 markers, "de novo" expression of CD150 and no detectable levels of either CD206 or MHCII. To evaluate whether this specific activated microglial phenotype was associated with changes in neuronal activity, the electrophysiological properties of pyramidal neurons of the hippocampus (CA3-CA1) were analysed in vivo. We found a lower excitability of the CA3-CA1 synapses and absence of long-term potentiation (LTP) in GFAP-IL10Tg mice. This study is the first description of a transgenic mouse with astrocyte-targeted production of the cytokine IL-10. The findings indicate that IL-10 induces a specific activated microglial phenotype concomitant with changes in hippocampal LTP responses. This transgenic animal will be a very useful tool to study IL-10 functions in the CNS, not only under basal conditions, but also after different experimental lesions or induced diseases. (C) 2014 Elsevier Inc. All rights reserved.